Evaluating the influences of confounding variables on benchmark dose using a case study in the field of ionizing radiation
Bibliographic record
Abstract
PURPOSE: A vast amount of data regarding the effects of radiation stressors on transcriptional changes has been produced over the past few decades. These data have shown remarkable consistency across platforms and experimental design, enabling increased understanding of early molecular effects of radiation exposure. However, the value of transcriptomic data in the context of risk assessment is not clear and represents a gap that is worthy of further consideration. Recently, benchmark dose (BMD) modeling has shown promise in correlating a transcriptional point of departure (POD) to that derived using phenotypic outcomes relevant to human health risk assessment. Although frequently applied in chemical toxicity evaluation, our group has recently demonstrated application within the field of radiation research. This approach allows the possibility to quantitatively compare radiation-induced gene and pathway alterations across various datasets using BMD values and derive meaningful biological effects. However, before BMD modeling can confidently be used, an understanding of the impact of confounding variables on BMD outputs is needed. METHODS: To this end, BMD modeling was applied to a publicly available microarray dataset (Gene Expression Omnibus #GSE23515) that used peripheral blood ex-vivo gamma-irradiated at 0.82 Gy/min, at doses of 0, 0.1, 0.5 or 2 Gy, and assessed 6 hours post-exposure. The dataset comprised six female smokers (F-S), six female nonsmokers (F-NS), six male smokers (M-S), and six male nonsmokers (M-NS). RESULTS: A combined total of 412 genes were fit to models and the BMD distribution was noted to be bi-modal across the four groups. A total of 74, 41, 62 and 62 genes were unique to the F-NS, M-NS, F-S and M-S groups. Sixty-two BMD modeled genes and nine pathways were common across all four groups. There were no differential sensitivity of BMD responses in the robust common genes and pathways. CONCLUSION: For radiation-responsive genes and pathways common across the study groups, the BMD distribution of transcriptional activity was unaltered by sex and smoking status. Although further validation of the data is needed, these initial findings suggest BMD values for radiation relevant genes and pathways are robust and could be explored further in future studies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".